The overall objective of this proposal is to develop a human immunodeficiency virus type 1 (HIV-1)-macaque model of infection and disease. The lack of an animal model of HIV-1 infection has hampered studies of HIV-1 pathogenesis as well as preclinical testing of antiretroviral drug candidates and vaccines. Previous studies have explored whether macaque species can be used as a model host for HIV-1 infection. While SIV infection of rhesus macaques is a heavily utilized and important surrogate model for investigating relevant concepts in HIV-1 pathogenesis and disease, rhesus macaques are an unsuitable host for HIV-1 because of blocks to viral replication, which are mediated by at least two known proteins, TRIM51 and APOBEC3G. Interestingly, the pig-tailed macaque is uniquely susceptible to HIV-1, and this species of macaque supports a smoldering infection for several years before the virus is cleared. Recent data suggest that the greater susceptibility of pig-tailed macaques to HIV-1 may be due to the absence of the post-entry block to viral infection of cells. Our preliminary data support these observations and further show that pig-tailed macaque primary peripheral blood mononuclear cells (PBMCs) are more susceptible to infection by HIV-1 than rhesus macaque PBMCs. Furthermore, our data demonstrate that an HIV-1 clone containing the SIVmne vif gene (HSIV-vif) is capable of replicating in pig-tailed macaque PBMCs nearly as efficiently as a highly pathogenic SIVmne variant. We therefore hypothesize that the pig-tailed macaque may be a suitable host for HIV-1 and that tropism for this species is primarily determined by the functional activity of vif. We further hypothesize that the HIV-1/SIV-vif chimeric virus will replicate and cause disease in pig-tailed macaques. To address the hypotheses, we will further characterize replication of the HSIV-vif chimera in pig-tailed macaque cell cultures. Secondly, we will determine if HIV-1/SIV-vif clones constructed from different HIV-1 subtypes will replicate in primary pig-tailed macaque CD4+ T-cells in order to gain further insight into the species-specific tropism of HIV-1. Finally, we will examine if the HIV-1/SIV-vif chimera replicates and causes CD4+ T-cell decline in pig-tailed macaques. If successful, this model will be a highly significant achievement that will serve to advance studies of HIV-1 pathogenesis as well as preclinical testing of novel antiretroviral therapies and vaccines. PUBLIC HEALTH RELEVANCE: Currently, there is no cure or preventative vaccine for human immunodeficiency virus type 1 (HIV-1), the primary cause of AIDS world-wide. If the proposed studies to develop an HIV-1 macaque model are successful, they will facilitate preclinical testing of novel antiviral therapies and vaccines against HIV-1, which is hampered by the lack of a suitable animal model of infection and disease.